vaccine prophylaxis and diagnostics of viral hepatitis in russia k.kyuregyan, m.mikhailov ФГБУ...

Vaccine prophylaxis and diagnostics of viral hepatitis in Russia

K.Kyuregyan, M.Mikhailov

ФГБУ «Институт полиомиелита и вирусных энцефалитов им.М.П.Чумакова»

Managua, November 26-28, 2014

I Russia-Nicaragua Symposium “Actual issues in diagnostic and vaccine prophylaxis of

infectious diseases”

High level of heterogeneity of hepatitis viruses.

New diagnostic tests and vaccines.New knowledge on biology of hepatitis viruses.

Social, economic and epidemiology changes in country and in the world.

Globalization and migration contribute to distribution of viral hepatitis infections.

Van Herck & Van Damme, Expert Rev Vaccines 2005; 4: 459–71.WHO, Hepatitis A, WHO/CDS/CSR/EDC/2000.7

Hepatitis A: changing epidemiology

Improvements in

sanitary conditions

Decrease in HAV circulation in children

Increase in number

of susceptible

adolescents and adults

Increase in

non-immune adults

Increase in number of symptomatic hepatitis A cases

Hepatitis A incidence in Russia in 1991-2013

165,5

11,2

110,1109,9

123,5

87,4

50,4

34 30,2

57,3

79,4

46,9

28,3 30 30,2

15,710,3 8,1 7,3 6,3 4,3 5,5 5,7

0

20

40

60

80

100

120

140

160

180

91 92 93 94 95 96 97 98 99 2000 01 02 03 04 05 06 07 08 09 2010 11 12 13

годы

0/00

00 2

32

3

45

Hepatitis A outbreaks

Carla Vizzotti

Ministerio de Salud de la Nacion.Argentina

Meeting of the Strategic Advisory Groupof Experts on Immunization (SAGE)

10-12 April 2012CCV/CICG, Geneva

Monitoring the impact of a single doseHepatatis A vaccine administration in Argentina

Hepatitis A incidence before and after single dose vaccination of children at age 1 year in Argentina (2000-

2011)

C. Vizzotti, 2012

Tyva Republic

Tyva Republic is situated at South of Siberia. Distance to Moscow: 4 668 кмTerritory – 170,500 км2

Population (as for 1.01.2014 г.) - 311 761

Data from state surveillance system (Rospotrebnadzor)

Incidence of hepatitis A in children in 2001-2013 (cases per 100000 children population)

МИНИСТЕРСТВО ЗДРАВООХРАНЕНИЯ И СОЦИАЛЬНОГО РАЗВИТИЯ РЕСПУБЛИКИ ТЫВА

П Р И К А З « 18 » июля 2012 г. №

____/___г. КызылО массовой иммунизации детей, подростков против вирусного гепатита АВ Республику Тыва при содействии ФГБУ «Институт полиомиелита и вирусных

энцефалитов им. М.П. Чумакова» РАМН в рамках научно-практического сотрудничества с Министерством здравоохранения и социального развития Республики Тыва и Управления Федеральной службы по надзору в сфере защиты прав потребителей и благополучия человека по Республике Тыва по вопросам профилактики вирусных гепатитов и клещевых вирусных энцефалитов направлена вакцина против вирусного гепатита А «Хаврикс» в количестве 39611 доз компанией ЗАО «Глаксо Смит Кляйн Трейдинг» на безвозмездной основе для иммунизации детей Республики Тыва в возрасте 3-8 лет.

Вакцина поступила 19.07.2012 г. в отделение вакцинопрофилактики Республиканского Центра СПИД.

В целях успешной организации на территории Республики Тыва массовой иммунизации детского населения против гепатита А

Incidence of hepatitis А (per 1000 000) in Tyva Republic before (2012) and after (2013-2014) single dose vaccination in children at age 3-8

years

97,4

3,7 1,6

242,6

6,4 0,90

50

100

150

200

250

300

2012 2013 01 - 10.2014

0/00

00

Всего

Дети > 14 лет

By 12.2012 87% children of 3-8 years were vaccinated (about 40 000 children).

After vaccination start hepatitis A incidence decreased 26-fold (in 2013) and 61-fold (in 2014) in total population; in children: 38-fold (in 2013) and 270-fold in 2014.

During 01.-10.2014 total 5 cases were registered: 2 imported cases and 3 cases in non-vaccinated adults

The introduction of the single-dose mass vaccination in areas with intermediate hepatitis A endemicity will reduce the short-term economic costs of health care and the most efficient use of budgetary resources by protecting vaccinated population for several years, and completed the vaccination course with the use of a booster dose will provide long-term (at several decades) immunity in vaccinated.

We need to continue long-term monitoring of the epidemiological situation in Argentina, as well as to accumulate a similar experience in other regions of the world with transition hepatitis A.

World population7 billion.

2 billon. Have markers of current or past HBV infection

300-400 mln. – chronic HBV infection

25% have risk of death from cirrhosis or HCC

WHO and CDC fact sheets, available at www.who.int and www.cdc.gov

Prevalence of HBV infection and its consequences

Hepatitis B recombinant vaccines

• Protective antigen - HBsAg

• HBV gene coding the protective surface antigen is inserted into yeast genome

HBsAgГен, кодирующий HBs Ag

Вирус гепатита ВУчасток ДНК вируса, кодирующий HBs Ag,

Ген, кодирующий HBs Ag,

встроен в ДНК дрожжевой

клетки

Ферментация дрожжевых клеток

Экстракция иочистка HBsAg

Формулированиевакцины

• Vaccination against hepatitis B is included in National vaccination Calendar in December 1997 (Newborn vaccination)

• National project «Health» - vaccination of adolescents and adults

• The proportion of susceptible to HBV individuals in total population is still high

Incidence of acute hepatitis B in Russia in 1994-2012 (cases per 100 000)

25,1

32,135,836,635,7

43,342,2

34,9

19,78

13,110,4

6,995,264,04 2,7 2,221,711,42

8,56

05

101520253035404550

годы

пок

азат

ели

заб

олев

аем

ости

гепатит В

Incidence of acute and chronic hepatitis B in Russia

6,99

14,01

5,26

14

4,04

14,19

2,7

14,39

2,2

13,27

1,71

12,95

1,42

12,6

0

2

4

6

8

10

12

14

16

2006 2007 2008 2009 2010 2011 2012

острый гепатит B

хронический гепатит B

Пок

азат

ель

на

100

000

нас

елен

ия

Prevalence of HBsAg in different age groups in 6 regions of Russia

Assessing the impact of mass vaccination against hepatitis B in Russia

• Flexible mathematical model to assess the morbidity and mortality associated with HBV;

• Natural history and outcomes of HBV infection;• Prevalence of hepatitis B markers in discrete groups (women

of childbearing age, children under five years of age and adults from thirty years old and older).

Goldstein ST, Zhou F, Hadler SC, et al. A mathematical model to estimate global Hepatitis B disease burden and vaccination

impact. Int J Epidemiol 2005;34: 1329-39.

Estimated number of cases of HBV infection and associated deaths, its outcomes depending performed and non performed vaccination

•  

Without vaccination

With vaccination Prevented Decrease, %

HBV infection, Total number of cases 212 075 - 405 438 20 711 - 40 493 191 364 - 364 945 90%

Cases of acute HBV infection 28 875 - 59 083 2 816 - 5 770 26 059 - 53 313 90%

Cases of chronic HBV infection 54 766 - 109 836 5 370 - 11 575 49 395 - 98 261 89 - 90%

HBV associated mortality:        

Acute hepatitis B 121 - 247 12 - 24 109 - 223 90%

Cirrhosis 4 223 - 8 411 414 - 886 3 809 - 7 524 89 - 90%

HCC 1 894 - 5 030 186 - 530 1 708 - 4 500 89 - 90%

Total number of deaths 6 238 - 13 688 612 - 1 441 5 626 - 12 247 89 - 90%

The dependence of the incidence of chronic hepatitis B and hepatitis B-associated mortality on the rate of “birth dose” coverage

Lack of proofreading activity of HBV polymerase

Frequency of synonymous substitutions in HBV genome: 2.1 х 10-5/ site/ year

Mutations in HBsAg: immune escape

Evolution of HBsAg detection methods

Generation Method Relative sensitivity

Particles per ml serum

Sensitivity, ng/ml

First AGID 1 1,0 х 1011 2000

Second CIE 5 2,0 х 1010 400

Reopheresis 5 2,0 х 1010 400

CFT 10 1,0 х 1010 200

RPHR 100 1,0 х 109 20

Express methods 100 1,0 х 109 20

Third RIA 40 000 0,5 х 106 0,05

ELISA 200 000 0,1 х 106 0,01

Occult HBV infection

• HBsAg -• Anti-HBc +/-• Anti-HBs +/-• HBV DNA +

HIV 1 : 2 000 000 donations

NAT

HCV 1 : 2 000 000 donations

NAT

HBV 1 : 205 000 donations

HBsAg /anti-HBc

1: 300 000 donations

NAT

Postransfusion infection residual risks

Diagnostic problem: Occult HBV infection (HBV DNA+, HBsAg-)

• Viral surface protein (HBsAg) – main serological marker of infection

Immunohistochemical staining: HBsAg in hepatocytes

Immunocytochemical staining monoclonal-HBs, conjugate – protein A with colloidal gold (15 nm)

Prevalence of occult HBV infection Years of study

HBsAg ELISA test sensitivity

Обследованные контингенты

N Prevalence of occult HBV, %

2004 0,1 ng/ml Non-HBV chronic hepatitis

59 52,5%

Blood donors 3232 0,31% Healthcare workers 532 0,56%

2007 0,01 ng/ml

IDU 837 1,67% Healthy population of endemic region

542 0,42 %

Hepatitis C patients 200 0

2009-2010

0,01 ng/ml + mutant HBsAg

Non-HBV chronic hepatitis

50 2%

Группа №

образца

Аминокислотные

замены в S-гене

Аминокислотные

замены в «а»-

детерминанте

(аа 124-148)

Вирусная

нагрузка HBV

(VERSANT HBV

DNA 3.0)

122 - - < 2000

853 T118A* - < 2000 782 - - < 2000 2 T118V - < 2000 4 T118V - < 2000 5 T118V - < 2000

Первичные

доноры крови

6 T118V - < 2000 1 T118V - < 2000 286 L22E - < 2000

Медицинские

работники 516 - - < 2000 6491 - - < 2000 731 L13S, K24E, Q56S - < 2000 805 L13S, K24E - < 2000 43 - - < 2000 85 - - < 2000 93 T118V - < 2000 98 - - < 2000 113 T118A* - < 2000 25 - - < 2000 20 - - < 2000 350 - - < 2000

2 T57I, T118V - < 2000

Внутривенные

наркоманы

3 T118A*, W172L V128A 3,5 x 104

* - мутация, описанная Carman W.F. как вариант HBV, «избегающий» воздействия анти-ВГВ иммуноглобулинами (Carman W.F., 1997)

HEPATITIS DELTA VIRUS (HDV)

Prevalence of HDV infection

Total number of registered patients with viral hepatitis: 2685 :

Chronic hepatitis В+D - 696Cirrhosis В+D - 116

AJ583872.dFr-55(Cameroon)AJ583873.dFr-56(Cameroon)AJ583878.dFr-70(Egypt)AF008375.EgyptAJ583874.dFr-59(Egypt)M84917.LebanonAJ583879.dFr-71 (Central African RebubliсAJ583881.dFr-74(Democratic Republic of Congo)AJ583867.dFr-4(Ghana)U81989.EthiopiaAF008347.Turkish-01AF008309.Albania-02AF008320.Greek-19AF008333.ArchangelosAF008319.RomaniaAJ309878.Ya-724Tyva.20Tyva.93M58629.NauruAJ309871.Yakut(Ya)-8AJ309873.Ya-30X77627.ChinaM92448.TaiwanTyva.81U81988.SomaliaAJ309876.Ya-51AF008374.RussiaAJ309872.Ya-12AJ583876.dFr-65(Romania)Tyva.25AJ583875.dFr-65(Romania)Tyva.84Tyva.107Tyva.68Tyva.47Tyva.109Tyva.7Tyva.40Tyva.53Tyva.90Tyva.29Tyva.71Tyva.30Tyva.36Tyva.46Tyva.58AF008371.US-23AJ583869.dFr-46(France)AF008372.French-02D01075.US-1AF008420.Italy-35AF008373.AfghanistanX85253.CagliariX04451.Italy-A20AF309420.MiyakoAB015444.Ok3-25AB015443.Ok2-05AB015445.Ok4-15AB015446.Ok5-01AB015447.Ok6-21AB015442.Okinawa (Ok) 1-18AF018077.Taiwan-TW-2bAJ309868.Ya-13AJ309879.Yakut-26AJ309869.Ya-29AJ309877.Ya-704AJ309880.Yakut-62AJ309875.Ya-63AJ309874.Ya-245X60193.Japan-SU19598.Taiwan-3AF104264.TW2476AJ583871.dFr-48(Cameroon)AJ583887.dFr-2020(Ivory Coast)AJ583884.dFr-1594(Angola)AJ583868.dFr-45(Cameroon)AJ583888.dFr-2066(Cameroon)AJ583885.dFr-1843(Gabon)AJ583882.dFr-644(Congo)AJ583889.dFr-2204(Ivory Coast)AJ583890.dFr-2301(Ivory Coast)AJ583886.dFr-1953(Cameroon)AJ583880.dFr-73(Ivory Coast)AJ583877.dFr-69(Ghambia)AJ583883.dFr-910(Mali)AJ583870.dFr-47(Guinea)AJ583891.dFr-2317(Guinea)L22061.ColombiaAB037949.VnzD8624AB037948.VnzD8349AB037947.VnzD8375L22063.Peru-1L22064.Peru-2

100

91

99

99

99

82

75

74

92

97

99

96

96

98

99

76

75

99

8694

8172

83

84

100 70

0.000.050.100.15

AJ583872.dFr-55(Cameroon)AJ583873.dFr-56(Cameroon)AJ583878.dFr-70(Egypt)AF008375.EgyptAJ583874.dFr-59(Egypt)M84917.LebanonAJ583879.dFr-71 (Central African RebubliсAJ583881.dFr-74(Democratic Republic of Congo)AJ583867.dFr-4(Ghana)U81989.EthiopiaAF008347.Turkish-01AF008309.Albania-02AF008320.Greek-19AF008333.ArchangelosAF008319.RomaniaAJ309878.Ya-724Tyva.20Tyva.93M58629.NauruAJ309871.Yakut(Ya)-8AJ309873.Ya-30X77627.ChinaM92448.TaiwanTyva.81U81988.SomaliaAJ309876.Ya-51AF008374.RussiaAJ309872.Ya-12AJ583876.dFr-65(Romania)Tyva.25AJ583875.dFr-65(Romania)Tyva.84Tyva.107Tyva.68Tyva.47Tyva.109Tyva.7Tyva.40Tyva.53Tyva.90Tyva.29Tyva.71Tyva.30Tyva.36Tyva.46Tyva.58AF008371.US-23AJ583869.dFr-46(France)AF008372.French-02D01075.US-1AF008420.Italy-35AF008373.AfghanistanX85253.CagliariX04451.Italy-A20AF309420.MiyakoAB015444.Ok3-25AB015443.Ok2-05AB015445.Ok4-15AB015446.Ok5-01AB015447.Ok6-21AB015442.Okinawa (Ok) 1-18AF018077.Taiwan-TW-2bAJ309868.Ya-13AJ309879.Yakut-26AJ309869.Ya-29AJ309877.Ya-704AJ309880.Yakut-62AJ309875.Ya-63AJ309874.Ya-245X60193.Japan-SU19598.Taiwan-3AF104264.TW2476

AJ583872.dFr-55(Cameroon)AJ583873.dFr-56(Cameroon)AJ583878.dFr-70(Egypt)AF008375.EgyptAJ583874.dFr-59(Egypt)M84917.LebanonAJ583879.dFr-71 (Central African RebubliсAJ583881.dFr-74(Democratic Republic of Congo)AJ583867.dFr-4(Ghana)U81989.EthiopiaAF008347.Turkish-01AF008309.Albania-02AF008320.Greek-19AF008333.ArchangelosAF008319.RomaniaAJ309878.Ya-724Tyva.20Tyva.93M58629.NauruAJ309871.Yakut(Ya)-8AJ309873.Ya-30X77627.ChinaM92448.TaiwanTyva.81U81988.SomaliaAJ309876.Ya-51AF008374.RussiaAJ309872.Ya-12AJ583876.dFr-65(Romania)Tyva.25AJ583875.dFr-65(Romania)Tyva.84Tyva.107Tyva.68Tyva.47Tyva.109Tyva.7Tyva.40Tyva.53Tyva.90Tyva.29Tyva.71Tyva.30Tyva.36Tyva.46Tyva.58AF008371.US-23AJ583869.dFr-46(France)AF008372.French-02D01075.US-1AF008420.Italy-35AF008373.AfghanistanX85253.CagliariX04451.Italy-A20AF309420.MiyakoAB015444.Ok3-25AB015443.Ok2-05AB015445.Ok4-15AB015446.Ok5-01AB015447.Ok6-21AB015442.Okinawa (Ok) 1-18AF018077.Taiwan-TW-2bAJ309868.Ya-13AJ309879.Yakut-26AJ309869.Ya-29AJ309877.Ya-704AJ309880.Yakut-62AJ309875.Ya-63AJ309874.Ya-245X60193.Japan-SU19598.Taiwan-3AF104264.TW2476AJ583871.dFr-48(Cameroon)AJ583887.dFr-2020(Ivory Coast)AJ583884.dFr-1594(Angola)AJ583868.dFr-45(Cameroon)AJ583888.dFr-2066(Cameroon)AJ583885.dFr-1843(Gabon)AJ583882.dFr-644(Congo)AJ583889.dFr-2204(Ivory Coast)AJ583890.dFr-2301(Ivory Coast)AJ583886.dFr-1953(Cameroon)AJ583880.dFr-73(Ivory Coast)AJ583877.dFr-69(Ghambia)AJ583883.dFr-910(Mali)AJ583870.dFr-47(Guinea)AJ583891.dFr-2317(Guinea)L22061.ColombiaAB037949.VnzD8624AB037948.VnzD8349AB037947.VnzD8375L22063.Peru-1L22064.Peru-2

100

91

99

99

99

82

75

74

92

97

99

96

96

98

99

76

75

99

8694

8172

83

84

100 70

0.000.050.100.15

I генотип ВГDТЫВА

Total population(by 2012.) – 307 000 persons

II генотип ВГD

III генотип ВГD

Prevalence of HDV markers in healthy population of Tyva Republic, % (N=1086)

Age, years N Anti-HDVn %

HDV RNAn %

< 1 97 0 0 0 0

1-4 109 0 0 0 0

5-9 113 0 0 0 0

10-14 107 2 1,9 0 1,9

15-19 105 4 3,8 4 1,9

20-29 102 4 3,9 3 2,9

30-39 103 5 4,9 3 2,3

40-49 112 6 5,4 1 0,7

50-59 115 2 1,7 1 0,8

> 60 123 4 3,3 2 1,6

Total 1086 27 2,5 14 1,3

Dr. Mikhail Balayan

August, 12, 1981 - Oral infection combined extracts containing stool samples from 9 patients with the second episode of hepatitis

Family Hepeviridae

Genome + RNA

Virion 30-34 nm

RNA length 7.2 kb

Stability Low

Infectious virus titer in feces

104 – 107

Hepatitis E virus

Russian Federation, 2013 92 cases 0,06/ 100 000

Belgorod region, 2013 33 cases 2,15/ 100 000

Anti-HEV IgG prevalence in6 regions of Russia (n=6000)

7,54,9

2,6 2,1

5,3

2,24,1

02468

% а

нти-

ВГЕ

1 2 3 4 5 6 7

возрастная структура анти-ВГЕ IgG

0

5

10

15

20

25

30

1 2 3 4 5 6 7

регионы

an

ti-

HE

V, %

до 19 лет

20 - 59 лет

> 60 лет

• 1 – Moscow region• 2 – Rostov region• 3 – Sverdlovsk region• 4 – Yakutiya• 5 – Tyva• 6 – Khabarovsk region• 7 – median for 6 regions

Данные ИПВЭ им М.П. Чумакова РАМН, 2010

R.H. Purcell, S.U. Emerson Hepatitis E: An emerging awareness of an old disease // J. Hepatol. 2008 48(3):494-503

3

Hepatitis E - zoonoses

Т

Three proofs that hepatitis E - zoonoses:1. HEV prevalence in animals;2. Elevated levels of detection of anti - HEV antibodies in pig farm workers;3. Confirmed cases of HEV transmission from animals to human.

4173ekat.1 4357ekat.3 4172ekat.1 4352ekat.3 4178ekat.1 4198ekat.2 4199ekat.2 4156ekat.1 4191ekat.1 4410sar.1 4591sar.3 4196ekat.2 4194ekat.2 5512arch.3 5525arch.3 5435arch.3 5320arch.1 5353arch.2 5376arch.2 5354arch.2 5374arch.2 4192ekat.2 4131ekat.1 4313ekat.3 AF455784 H.3g 4952khab.3 AF336296 3f AY323506 3f AF332620 3f AY032758 3f AY032757 3f AY362357 H.3e AF503512 3e AB094231 3e AB073911 3e 4835khab.1 4892khab.1 5107kalin.1 5151kalin.2 5109kalin.1 5130kalin.2 3990vlad 3950vlad 3951vlad 3968vlad 3974vlad 3973vlad 3948vlad AB105903 S.3a AP003430 H.3b AF296167 H.3d AY115488 S.3j 4586sar.2 4631sar.3 4610sar.3 4677sar.3 4539sar.2 4863khab.1 4502sar.2 4579sar.2 FJ998010 3i FJ998012 3i AF336293 3c AF336290 S.3c AF336298 3c AF336297 3c AB097811 Japan HEV type IV M74506 HEV2 Mexico DQ450072 China HEV type IV AY723745 India HEV type IV

AY594199 China HEV type IV M73218 Burma H. E virus type I D10330 Burma HEVNE8L type I AF051830 Nepal HEV TK15/92 type I X99441 India HEV type I X98292 India hev037 type I M80581 Pakistan HEV type I D11093 China HEV type I L25547 China HEV type I M94177 China HEV type I

88100

7690

100

98

100

100

87

100

95

100

80100

100

100

100

98100

100

100

97

91

100

100

98

100

87

98

98

78

100

0.000.020.040.060.080.10

Гено

тип

3 ВГ

Е

Phylogenetic tree for HEV isolates from pigs: Archangelsk region, Vladimir region, Kaliningrad region, Saratov region, Sverdlovsk region, Khabarovsk region

Detection of HEV infection in pigs

18,2

69,5

50

15,8

000

10

20

30

40

50

60

70

80

0-30 31-60 61-90 91-120 121-150 > 150

В озрас т жив отны х, дни

РН

К В

ГЕ

%

Vaccine against hepatitis EVaccine Producent Trial phase N

participantsEfficacy

56 kDa ORF2 HEV1

Insect cells II 898 95,5%

26 kDa ORF2 HEV1

E. coli II 457 83%

III 56,302 100%

Vaccine was protective against HEV genotypes 3&4 in pigs and rabbits challenge experiments – veterinary vaccine

ФЕДЕРАЛЬНОЕ ГОСУДАРСТВЕННОЕ БЮДЖЕТНОЕ УЧРЕЖДЕНИЕ ИНСТИТУТ ПОЛИОМИЕЛИТА И ВИРУСНЫХ ЭНЦЕФАЛИТОВ ИМЕНИ М.П.ЧУМАКОВА РОССИЙСКОЙ АКАДЕМИИ МЕДИЦИНСКИХ НАУК